A wide variety of 5-acyl-1-hydrocarbylpyrrole-2-acetic acids are known to possess useful pharmacological properties. For example, 1-methyl-5-p-toluoylpyrrole-2-acetic acid has a marked anti-inflammatory activity [J. Pharmacology and Experimental Therapeutics, 185, 127 (1973)]. See also U.S. Pat. Nos. 3,752,826; 3,755,307; 3,803,169; 3,803,171 and 4,048,191 (the disclosures of which are incorporated herein) which describe, inter alia, numerous 5-acyl-1-hydrocarbylpyrrole-2-acetic acids having anti-inflammatory and analgetic activities.
In copending application Ser. No. 963,673, filed Nov. 27, 1978 (the disclosure of which is incorporated herein), Kondo, Suda and Tunemoto describe a novel and useful three-step synthesis for producing 5-acyl-1-hydrocarbylpyrrole-2-acetic acid. In the second step of this process, a novel compound--viz., a 5-cyano-1-hydrocarbylpyrrole-2-acetic acid--is produced by reacting 2,2,2-trichloro-1-(N-hydrocarbylpyrryl-2)-ethanol, also known as 1-hydrocarbyl-(2',2',2'-trichloro-1'-hydroxyethyl)-pyrrole, with a cyanating reagent under basic conditions, preferably in a solvent. Examples of the solvent used for this reaction are alcohols such as methanol and ethanol, ethers such as ether, dioxane, THF, and like polar solvents such as dimethyl formamide, dimethyl sulfoxide, and sulfolane, and their mixed solvent with water. Kondo et al. indicate that in this reaction the best results have been obtained using a mixture of methanol and water as the reaction solvent, that the reaction proceeds at or under room temperature, and that, if necessary, the reaction mixture can be heated.
Examples of the cyanating reagent used in their process include inorganic cyanides such as potassium cyanide, sodium cyanide, cuprous cyanide, and the like, and acetone cyanohydrin and the like. To establish the basic reaction conditions, Kondo et al. prefer that the cyanation be performed in the presence of alkali metal salts such as sodium carbonate, potassium carbonate and the like; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like; or alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, and the like (in this case, the presence of water is essential). Use of sodium hydroxide or potassium hydroxide is most preferred.
Another way of achieving the basic conditions for the Kondo et al. reaction involves use of a large amount of the cyanating reagent when it itself is a base.
As pointed out in the foregoing application, when the reaction of the 2,2,2-trichloro-1-(N-hydrocarbylpyrryl-2)-ethanol with the cyanating reagent is performed under the above conditions and when the acidic product is separated from the resulting reaction mixture, for example, by extraction with alkali and subsequent acidification, the desired 5-cyano-1-hydrocarbylpyrrole-2-acetic acid can selectively be obtained.
While the foregoing process represents a distinct contribution to the art, it nevertheless does possess several drawbacks. To achieve optimum yields large excesses of cyanating reagents were used, NaOH or KOH was added to the reaction mixture on a periodic basis during the reaction, and long reaction times were employed. For instance, in their Example 6, 2,2,2-trichloro-1-(N-methylpyrryl-2)-ethanol was reacted with sodium cyanide (500% excess) in aqueous methanol at 30.degree.-35.degree. C. while feeding aqueous potassium hydroxide (33% excess) over a 20-hour period. After an additional two hours of reaction, the 5-cyano-1-methylpyrrole-2-acetic acid was obtained in 58 percent yield. Further, to recover the product from the reaction solution, the procedure used involved diluting the reaction mixture with water, washing with methylene chloride, carefully acidifying the aqueous layer with HCl, extracting the acidified layer with methylene chloride, washing the extracts with brine, drying the extracts over magnesium sulfate, concentrating the dried extract, and then subjecting the extract to chromatography on silica gel using a hexane-ethyl acetate eluent. Besides involving a number of operations, such a recovery procedure suffers from the hazards of HCN generation during the acidification step.